Liver cancer is the 2nd leading cause of cancer-related deaths worldwide. The 5-year survival rate for liver cancer remains extremely low due to inadequate methods for detecting and treating this disease. Infection with hepatitis C virus (HCV) is the primary cause of liver cancer in the United States, and the incidence of HCV- associated liver cancer is projected to rise in coming decades. Nonetheless, the manner in which HCV infection promotes carcinogenesis remains undefined, and our limited knowledge of this process poses a critical barrier for developing new therapies to combat HCV-associated liver cancer. Mounting evidence from our laboratory suggests that HCV infection contributes directly to liver carcinogenesis by disrupting host tumor suppressor pathways. In particular, we have recently discovered that HCV infection represses the host DNA damage response (DDR). This response plays a central role in tumor suppression by detecting damaged DNA and mediating DNA repair. Conversely, disruption of the DDR causes genomic instability and carcinogenesis. Thus, we propose that HCV infection contributes to liver carcinogenesis by inhibiting the host DDR. Our preliminary data indicate that HCV infection represses the host DDR by restricting the activation of ATM, one of the key kinases that initiate the DDR. ATM activation is typically guided by the cellular Mre11/Rad50/Nbs1 (MRN) complex, which binds directly to damaged DNA and recruits ATM for activation. Therefore, we hypothesize that HCV infection restricts ATM activation by impairing the function of the host MRN complex. To address this hypothesis, we will probe the effects of HCV infection on MRN complex assembly and MRN- dependent activation of ATM. Importantly, recent studies have demonstrated that the DDR regulates a wide- array of cellular processes following DNA damage. These findings suggest that repression of the host DDR likely alters cellular signaling on a broad level during HCV infection, possibly disrupting other critical tumor suppressor pathways. As such, we propose an unbiased, proteomics-based approach to identify global changes in DDR-regulated signaling following HCV infection.